In an article responding to commentaries on the Emperor’s New Drugs study “Antidepressants and Placebos: Secrets, Revelations, and Unanswered Questions,” Kirsch et al. stated that “there is now unanimous agreement among commentators that the mean difference between response to antidepressant drugs and response to inert placebo is very small. It is so small that, despite sample sizes involving hundreds of participants, 57% of the trials funded by the pharmaceutical industry failed to show a significant difference between drug and placebo. Most of these negative data were not published (see Thase, 2002) and were accessible only by gaining access to U.S. Food and Drug Administration (FDA) documents.” The authors go on to state:

The small difference between the drug response and the placebo response has been a “dirty little secret” (Hollon, DeRubeis, Shelton, & Weiss, 2002), known to researchers who conduct clinical trials, FDA reviewers, and a small group of critics who analyzed the published data and reached conclusions similar to ours (e.g., Greenberg & Fisher, 1989). It was not known to the general public, depressed patients, or even their physicians.1 We are pleased that our effort facilitates dissemination of this information.” (Id.)

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FN 1. An internal memorandum by the Director of the Division of Neuropharmacological Drug Products indicates FDA awareness of this situation:

The Clinical Efficacy Trials subsection within the Clinical Pharmacology section not only describes the clinical trials providing evidence of citalopram’s antidepressant effects, but make mention of adequate and well controlled clinical studies that failed to do so. I am mindful, based on prior discussions of the issue, that the Office Director is inclined toward the view that the provision of such information is of no practical value to either the patient or prescriber. I disagree. I believe it is useful for the prescriber, patient, and 3rd-party payer to know, without having to gain access to official FDA review documents, that citalopram’s antidepressants (sic) effects were not detected in every controlled clinical trial intended to demonstrate those effects. I am aware that clinical studies often fail to document the efficacy of effective drugs, but I doubt that the public, or even the majority of the medical community, is aware of this fact. I am persuaded that they not only have a right to know but that they should know. Moreover, I believe that labeling that selectively describes positive studies and excludes mention of negative ones can be viewed as potentially “false and misleading” (Lever, 1998, p.11).

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The paper goes on to state:

“In the meantime, what are the alternatives for treating patients? Imagine having a choice between four treatments. Treatment A produces a large therapeutic response but also a large number of adverse effects, including diarrhea, nausea, anorexia, sweating, forgetfulness, bleeding, seizures, anxiety, mania, sleep disruption, and sexual dysfunction. Treatments B and C produce therapeutic responses that are almost as great as those produced by treatment A, but without the adverse effects. In fact, the side effects produced by Treatment B are beneficial (e.g., better general physical health). However, the therapeutic effects of Treatments B and C have been evaluated in relatively few studies. Treatment D has been assessed in many comparative studies, in which it has been found to be as effective as Treatment A in the short term and more effective in the long term. It does not produce adverse effects. Given a choice between these alternatives, which would you choose?

Of course, these alternatives are not merely hypothetical. Treatment A corresponds to SSRIs, and the list of side effects is drawn from those that have been shown to be produced by these medications (Antonuccio, Danton, DeNelsky, Greenberg, & Gordon, 1999; Mulrow et al., 1999). Treatment B is physical exercise, which has been reported to have lasting therapeutic benefits in the treatment of major depression (Babyak et al., 2000). It may be nothing more than a placebo, but if so, it is one with desirable rather than adverse side effects. Treatment C is bibliotherapy (e.g., Burns, 1999), another low-cost treatment with demonstrated effectiveness (Jamison & Scogin, 1995; Smith, Floyd, Jamison, & Scogin, 1997) and little danger of side effects. Treatment D is psychotherapy. As noted by Antonuccio et al.(2002), “psychotherapy (particularly cognitive therapy, behavioral activation, and interpersonal therapy) compares favorably with medications in the short term, even when the depression is severe (e.g., DeRubeis, Gelfand, Tang, & Simons, 1999), and appear superior to medications in long-term comparative studies (Antonuccio et al. 1995; Hollon, Shelton, & Loosen, 1991)” ( 24). Given these data, antidepressant medication might best be considered a last resort, restricted to patients who refuse or fail to respond to other treatments.”

In fact, in every independent study, exercise proved to be more effective than antidepressants in decreasing depression. It should also be noted that 15% of the paid volunteers in the clinical trials stopped taking the drug because they could not tolerate the side effects.

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